Correlation Between the Kinetics of CD3+ Chimerism and the Incidence of Graft-Versus-Host Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
ABSTRACT Graft-versus-host disease (GvHD) remains a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment may improve patient outcomes. A prospective study to investigate the relationship between chimerism kinetics and the development of acute or chronic GvHD was carried out. Split chimerism in association with the onset of GvHD was also analyzed.
Thirty-three patients with hematologic diseases treated with allogeneic HSCT were analyzed. They were conditioned with myeloablative or reduced intensity regimens and grafted with peripheral blood (PB) or bone marrow stem cells. GvHD prophylaxis consisted of cyclosporine and methotrexate. Chimerism evaluation was performed on PB mononuclear cells and purified cell subsets consisting of separated CD3(+) T cells, monocytes (CD14(+)), and granulocytes (CD15(+)). Chimerism analysis was performed at 30, 60, 120, and a median of 200 days after HSCT.
Acute GvHD was diagnosed in 19 patients and chronic GvHD in 16. On day 30, no relation was found between the level of donor chimerism and aGvHD. Upon univariate analysis, decreasing mixed chimerism among CD3(+) and infused CD34(+) cell numbers was significantly correlated with acute GvHD development, while the PB stem cell source, reduced-intensity conditioning regimen, and female donor sex were associated with an increased risk of chronic GvHD. In multivariate analysis, the risk of acute GvHD correlated only with the CD34(+) cell dose, while the risk of extensive chronic GvHD was associated with high CD3(+) donor chimerism on day 30. Patients with versus without split chimerism (T cell vs myeloid lines) did not differ statistically in their incidence of acute GvHD or chronic GvHD.
Our results supported the belief that chimerism kinetics or longitudinal chimerism evaluation is of greater significance than isolated absolute values of the percentage of chimerism at a single point after HSCT. The observations suggest that longitudinal monitoring of chimerism in CD3(+) T-cell subsets is an acceptable method to predict the development of GvHD among patients undergoing HSCT.
[Show abstract] [Hide abstract]
ABSTRACT: Double umbilical cord blood (dUCB) allogeneic transplantation following low dose Total body irradiation, Cyclophosphamide and Fludarabine (TCF regimen)-based reduced-intensity conditioning regimen (RIC) is increasingly used in adults lacking a suitable related or unrelated donor. Currently, there is little data regarding the impact on long-term outcome of CD3+ T cell chimerism (TCC) in this particular setting. Thirty-six adults with various hematological diseases and who received dUCB allogeneic transplant conditioned with TCF were included in this retrospective study. Peripheral blood CD3+ TCC was considered until day +100 post-tranplant in order to determine the impact of full versus mixed chimerism on long-term outcomes. Twenty-nine and 7 patients were documented with full and mixed CD3+ TCC, respectively, within the first 100 days post-transplant. With a median follow-up of 36 months, 3 year-overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) were 61%, (95% CI: 43-75); 50% (95% CI: 32.5-66) and 28% (95% CI: 16-44), respectively. In univariate analysis, a full CD3+ TCC was associated with a better 3-year DFS : 59% (95% CI: 39-75.5) vs 14% (95% CI: 7-46), (HR=0.24 [0.09-0.65], p=0.005) and a lower CIR: 24% (95% CI: 21.5-57) vs 78% (95% CI: 52-99), (HR=0.18 [0.05-0.5], p=0.004). In multivariate analysis, a full CD3+ TCC remained associated with a lower CIR (HR=0.17 [0.028-0.99], p=0.049). CD3+ TCC has no impact on graft versus host disease and non-relapse mortality in this study. In conclusion, here, full CD3+ TCC was independently associated with a lower risk of relapse in adults receiving a dUCB TCF RIC allogeneic transplant. This highlights the need to develop immunotherapy approaches allowing for early conversion to full chimerism after this type of transplant.Biology of Blood and Marrow Transplantation 01/2014; 21(1). DOI:10.1016/j.bbmt.2014.08.018 · 3.35 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Chimerism dynamics in bone marrow, peripheral blood (PB), and T lymphocytes (TLs) has been associated with the development of various complications after allogeneic stem-cell transplantation (allo-SCT). In the present study, the usefulness of chimerism monitoring in CD25(+)-activated leukocytes (ALs), together with that in bone marrow, PB, and TLs, for the anticipation of complications after allo-SCT, has been analyzed in 68 patients. In ALs, we observed a slower dynamics toward complete chimerism (CC) than in PB (p = 0.042), while no significant differences were found between TLs and PB (p = 0.12). Complete chimerism achievement in AL at day +30 has shown to be an independent risk factor for the development of grade II-IV acute graft-versus-host disease (aGvHD; hazard ratio [95% confidence interval]: 11.9 [1.5-91.7]; p = 0.017). Moreover, among patients achieving CC in TLs and ALs at different time-points after SCT (n = 17/68), the incidence of grade II-IV aGvHD was significantly higher in patients who achieved CC earlier in ALs (5/5) than in those who achieved CC earlier in TLs (1/11; p = 0.001). Therefore, achievement of early complete donor chimerism in CD25(+) ALs is a strong predictor for the development of aGvHD. Prospective analysis of chimerism in ALs could improve the post-SCT management of immunosuppressive therapy in transplanted patients. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.Experimental Hematology 10/2014; 43(1). DOI:10.1016/j.exphem.2014.09.003 · 2.81 Impact Factor
Article: Monitoring of chimerism following allogeneic haematopoietic stem cell transplantation (HSCT): Technical recommendations for the use of Short Tandem Repeat (STR) based techniques, on behalf of the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping Chimerism Working Group.[Show abstract] [Hide abstract]
ABSTRACT: Analysis of short tandem repeats (STR) is the predominant method for post-transplant monitoring of donor engraftment. It can enable early detection of disease relapse, level of engraftment and provide useful information on the graft-versus-host disease (GVHD)/graft-versus-tumour (GVT) effect, facilitating therapeutic intervention. Harmonization and standardization of techniques and result interpretation is essential to reduce the impact of laboratory variability on both clinical management and the results of multi-centre clinical trials. However, the United Kingdom National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI) has highlighted significant issues inherent in STR testing that impact upon inter- and intra- laboratory variation. We present here consensus best practice guidelines and recommendations for STR chimerism testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 11 UK and Eire clinical laboratories. This document uses data obtained from the UK NEQAS LI Post-Stem Cell Transplant (SCT) Chimerism Monitoring Programme.British Journal of Haematology 08/2014; DOI:10.1111/bjh.13073 · 4.96 Impact Factor